Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations
2016 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197Article in journal (Refereed) Epub ahead of print
Context: Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, premature growth cessation and minor skeletal abnormalities.
Objective: Characterize the phenotypic spectrum, associated conditions and response to growth-promoting therapies.
Design: Retrospective international cohort study.
Patients: Information from 103 individuals (57 female, 46 male) from 20 families with confirmed heterozygous ACAN mutations were included.
Methods: Families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next generation sequencing, and/or Sanger sequencing. Clinical information was collected from medical records.
Results: Identified ACAN variants showed perfect co-segregation with phenotype. Adult individuals had mildly disproportionate short stature (median height: -2.8 SDS, range: -5.9 to -0.9) and histories of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). There was no apparent genotype-phenotype correlation between type of ACAN mutation and presence of joint complaints. During childhood, height was less affected (median height: -2.0 SDS, range: -4.2 to -0.6). In contrast to most children with short stature, the majority of children had advanced BA (BA - CA, median: +1.3y; range +0.0 to +3.7y) reflecting a reduction in remaining growth potential. Nineteen individuals had received GH with some evidence of increased growth velocity.
Conclusions Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. In several of the families, affected individuals developed early-onset osteoarthritis and degenerative disc disease requiring intervention, suggesting dysfunction of articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
Place, publisher, year, edition, pages
Cary, USA: Oxford University Press, 2016.
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:oru:diva-53667DOI: 10.1210/jc.2016-3313PubMedID: 27870580OAI: oai:DiVA.org:oru-53667DiVA: diva2:1050183